ABSTRACT Our genome-metabolome investigations of type 2 diabetes (T2D) and the associated cardiometabolic (CM) complications are one of the high-priority research areas for the NIH to understand the causes of disparities in health in underserved populations of the US. T2D prevalence is projected to increase from 10% currently to 33% by the year 2050 in the US. South Asians (SAs) are a rapidly growing ethnic minority group, and have a well-documented high predisposition to T2D and cardiovascular diseases. Although it is well known that genetic and environmental factors influence T2D, the underlying mechanisms are poorly characterized in SAs. Recent studies performed in European populations have identified genetic factors influencing metabolite concentrations in patients with a wide spectrum of cardiometabolic diseases using metabolome-wide/genome-wide technologies. However, no such study has ever been performed in any population from India despite the fact that about one in four people in the global population are part of the SA population. Unlike conventional genome-wide association studies (GWAS), the metabolome GWAS (mGWAS) has higher statistical power to capture common genetic variation. Given the promise of the genome-metabolome approaches in elucidating underlying genetic causes for disease, such investigations in other non-white ethnic cohorts are critical to achieve advances in precision medicine. Essentially, such studies will help characterize unique metabolites linked with the ?non- obese/metabolically-obese? phenotype of T2D in SAs and others. Therefore in this investigation, using existing resources of already collected family and population-based samples (n=5,250) from the Asian Indian Diabetic Heart Study (AIDHS), our strategy is to cost-effectively integrate phenotypic, metabolomic, and genomic data to investigate the underlying genetic mechanisms regulating T2D pathophysiology. We propose these three specific aims for this proposal: AIM 1: Generate global (untargeted) metabolome profiles to identify and characterize small heritable molecules genetically correlated with T2D and related cardiometabolic traits using GCxGC-MS; AIM 2: Perform mGWAS to identify mQTLs and variants simultaneously associated with T2D, metabolites, and other traits; Replicate association of the top mQTL variants and ~15-20 of most significant metabolites in additional independent SA samples; AIM 3: Determine differences and similarities of putative biomarkers for T2D by performing look-up analysis in US multiethnic families, and perform preliminary functional characterization of a few of the most interesting mQTL loci by using zebrafish and knockout mouse models. OVERALL IMPACT: No comparable study has ever been undertaken in people of Asian Indian descent. With our outstanding team, a unique high-risk homogenous Sikh population, and cost-effective utilization of existing resources, our project has high potential to identify novel biomarkers of therapeutic importance. Of these, some may predict a subtype of T2D risk linked to early onset at lower obesity thresholds in relevance to multi-ethnic US populations.